PT99368A - PROCESS FOR THE PREPARATION OF PIPERAZINE DERIVATIVES - Google Patents
PROCESS FOR THE PREPARATION OF PIPERAZINE DERIVATIVES Download PDFInfo
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- PT99368A PT99368A PT99368A PT9936891A PT99368A PT 99368 A PT99368 A PT 99368A PT 99368 A PT99368 A PT 99368A PT 9936891 A PT9936891 A PT 9936891A PT 99368 A PT99368 A PT 99368A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- General Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
A presente invenção refere-se a um novo processo para a preparação de derivados de piperazina e dos seus* sais.The present invention relates to a novel process for the preparation of piperazine derivatives and their salts.
Mais particularmente, a presente invenção refere-se à preparação de deávados de piperazina da fórmula (I),More particularly, the present invention relates to the preparation of piperazine derivatives of formula (I),
(I) em que R representa um átomo de hidrogénio ou um grupo metilo, e os seus sais. E sabido que os compostos de fórmula (I) influenciam a entrada de iões de cálcio e podem ser vantajosamente usados para o tratamento de doenças cardiovasculares , tais como o enfarte do miocárdio, congestão cardíaca, angina e arritmia. A preparação dos compostos acima referidos é descrita na memória da patente Húngara ne 192. 404. Os autores descrevem duas variantes de processo. Ambas as variantes partem dos mesmos materiais de partida. A diferença entre as duas variantes de processo reside no facto de os grupos substituintes nos dois átomos de azoto do anel de piperazina, serem, introduzidos em sequências diferentes. A desvantagem de ambas as variantes é a via de sintese linear, que não é vantajosa numa síntese de mais fases deste tipo, uma vez que os rendimentos re-(I) wherein R represents a hydrogen atom or a methyl group, and salts thereof. It is known that the compounds of formula (I) influence the calcium ion input and may be advantageously used for the treatment of cardiovascular diseases, such as myocardial infarction, cardiac congestion, angina, and arrhythmia. The preparation of the above-mentioned compounds is described in the Hungarian patent specification no. 192 404. The authors describe two process variants. Both variants depart from the same starting materials. The difference between the two process variants is that the substituent groups on the two nitrogen atoms of the piperazine ring are introduced in different sequences. The disadvantage of both variants is the linear synthesis pathway, which is not advantageous in a synthesis of more phases of this type, since the re-
VV
" ίψ.-, j'· / -Λ // /4^ a - - /.r /' í ·.. ..-·· c lacionados com os materiais de partida são demasiado baixos no final da síntese." The compounds of formula (I) with the starting materials are too low at the end of the synthesis.
Uma outra desvantagem destes processos consiste na necessidade de usar a piperazina em grande excesso, a fim de evitar a reacção secundária no outro átomo de azoto do anel. 0 objectivo da presente invenção consiste em proporcionar um processo para eliminar as desvantagens acima referidas e preparar os produtos finais com rendimentos elevados. A presente invenção baseia-se no reconhecimento de que, se os compostos das fórmulas (II) e (III) forem preparados irt-dependentemente, uns dos outros por métodos em si conhecidos, e se o anel de piperazina fôr formado a partir destes compostos como uma fase de fechamento do processo, obtem-se um produto final puro e de elevada qualidade com rendimentos favoráveis.A further disadvantage of these processes is the need to use the piperazine in large excess in order to avoid the secondary reaction at the other ring nitrogen atom. The object of the present invention is to provide a process for eliminating the above-mentioned drawbacks and preparing the end products in high yields. The present invention is based on the recognition that if the compounds of the formulas (II) and (III) are prepared in a manner dependent on each other by methods known per se and the piperazine ring is formed from these compounds as a process closure step, a pure, high quality final product is obtained in favorable yields.
Deste modo, a presente invenção refere-se a um processo para a preparação de derivados de piperazina da fórmula (I) e dos seus sais — na fórmula R representa um átomo de hidrogénio, ou um grupo metilo —fazendo reagir um composto de amina da fórmula (II) 3Accordingly, the present invention relates to a process for the preparation of piperazine derivatives of the formula (I) and salts thereof - in the formula R represents a hydrogen atom, or a methyl group - by reacting an amine compound of the formula formula (II) 3
OCHOCH
NH.NH.
OH (II) 7OH (II) 7
com um composto de fórmula (III),with a compound of formula (III),
RR
» ci x CIV_y (III) em que R é tal como se defeniu acima, ou com um seu sal de adição de ácido.(III) wherein R is as defined above, or with an acid addition salt thereof.
De acordo com uma forma de realização preferida do processo da presente invenção, a reacção é levada a cabo no seio de um dissolvente orgânico miscível com água, tal como acetona. E especialmente preferido o uso, como meio reaccional, de uma mistura de 30 a 60% em volume de acetona e água. 0 composto da fórmula (II) é conhecido e pode ser preparado por exemplo, a partir de um derivado de oxirano apropriado, conforme descrito in J. Med. Chem., 9, 155 (1966). 0 composto da fórmula (III), em que R representa hidrogénio, é também conhecido e pode ser preparado tal como se descreve in Can. J. Chem. 45, 155 (1967) a partir de cloridrato de N,N-bis-(2-cloroetil)-amina, ou fazendo reagir um derivado de bis-(2-hidroxietil)amino, correspondente, com cloreto de tionilo. 0 composto da fórmula (III), em que R representa um grupo metilo, 6 novo. Pode ser preparado de forma análoga.According to a preferred embodiment of the process of the present invention, the reaction is carried out in a water-miscible organic solvent, such as acetone. Especially preferred is the use, as the reaction medium, of a mixture of 30 to 60% by volume of acetone and water. The compound of formula (II) is known and may be prepared for example from an appropriate oxirane derivative as described in J. Med. Chem., 9, 155 (1966). The compound of formula (III), wherein R represents hydrogen, is also known and can be prepared as described in Can. J. Chem. 45, 155 (1967) from N, N-bis- (2-chloroethyl) -amine hydrochloride, or by reacting a corresponding bis- (2-hydroxyethyl) amino derivative with thionyl chloride. The compound of formula (III), wherein R represents a methyl group, It can be prepared in an analogous way.
Durante a realização do processo da presente invenção, são usados água e um dissolvente orgânico miscível com água, como dissolvente, na forma de misturas de composição diferente de preferência acetona contendo 30 a 60% de água, ao ponto de ebulição. Como agente de ligação de ácido é apropriado o uso de bases orgânicas diferentes, de preferência trietilamina, ου uma base inorgânica, por exemplo, uma solução aquosa de hidróxido de sódio.During the process of the present invention water and a water miscible organic solvent are used as the solvent in the form of mixtures of different composition preferably acetone containing 30 to 60% water at the boiling point. As the acid binding agent, the use of different organic bases, preferably triethylamine, is suitable for an inorganic base, for example an aqueous solution of sodium hydroxide.
De acordo com uma forma de realização preferida da preserv-te invenção, fazem-se ferver, numa proporção equimolar, o composto da fórmula (III) ou um seu sal de cloridrato e o composto da fórmula (II) usados como materiais de partida, na presença de trietilamina, numa quantidade suficientemente elevada para ligar o ácido formado, em acetona aquosa a 50%, durante 1 a 3 horas; em seguida, a acetona é removida por destilação e o produto é extraído da fase aquosa com um dissolvente orgânico.According to a preferred embodiment of the present invention, the compound of formula (III) or a hydrochloride salt thereof and the compound of formula (II) used as starting materials are boiled in an equimolar proportion, in the presence of triethylamine in an amount sufficiently high to link the acid formed in 50% aqueous acetone for 1 to 3 hours; then the acetone is removed by distillation and the product is extracted from the aqueous phase with an organic solvent.
Se se desejar, o produto é submetido a cromatografia, ou é purificado por formação de sal.If desired, the product is chromatographed, or purified by salt formation.
As vantagens do processo da invenção podem ser sumariza-das da seguinte forma: -o processo pode ser realizado de maneira simples; e -os requisitos dos materiais de partida podem ser diminuídos preparando-se as duas partes da molécula independentemente uma da outra.The advantages of the process of the invention can be summarized as follows: the process can be carried out in a simple manner; and the requirements of the starting materials may be decreased by preparing the two parts of the molecule independently of one another.
é explicado por meio dos exemplos 0 processo da invenção não limitativos seguintes:is explained by the following non-limiting examples of the process of the invention:
Exemplo 1 propj]T|-Example 1 propyl]
Dicloridrato de 1--4-ffenil- aminocarboni 2-metoxifenoxi)-2-hidroxi 1) piperazina.1- 4-Phenylaminocarbonyl 2-methoxyphenoxy) -2-hydroxy-1) piperazine dihydrochloride.
Pesam-se num balão de fundo redondo, com um volume de 50 cm , 0,82 g (0,003 mole) de cloridrato de c*í-£n , N-bis (2-clo-roetil) -amino^j - acetanilida, 20 cm de acetona aquosa a 50%, 0.6 g (0,003 mole) de 1- £3-(2-metoxifenoxi)-2-hidroxipropilj amina e 0,9 g (1,25 cm , 0,009 moles) de trietilamina. Ferve--se a mistura durante 2 horas, depois arrefece-se para a temperatura ambiente e destila-se a acetona em vácuo. Extrai-se 3 a fase aquosa residual duas vezes com 10 cm de clorofórmio, de cada vez. Seca-se a fase orgânica e evapora-se. Dissolve-se 3 o óleo residual em 2 cm de metanol e acidifica—se até um pH de 2 , adicionando ácido clorídrico metanólico. Filtra-se o produto do título cristalino precipitado e seca-se. Rendimento: 0,85 g (60,0%), ponto de fusão: 207-211^0. '10.82 g (0.003 mole) of N, N-bis (2-chloroethyl) -amino] -acetanilide hydrochloride (0.82 g, 0.003 mole) is weighed into a round-bottomed flask , 20 cm @ 3 of 50% aqueous acetone, 0.6 g (0.003 mol) of 1- (3- (2-methoxyphenoxy) -2-hydroxypropyl) amine and 0.9 g (1.25 cm, 0.009 mol) of triethylamine. The mixture is boiled for 2 hours, then cooled to room temperature and acetone is distilled off in vacuo. The residual aqueous phase is extracted twice with 10 cm of chloroform each time. The organic phase is dried and evaporated. The residual oil is dissolved in 2 cm @ 3 of methanol and acidified to pH 2 by adding methanolic hydrochloric acid. The precipitated crystalline title product is filtered off and dried. Yield: 0.85 g (60.0%), m.p. 207-211 ° C. '1
Exemplo 2 a) pç- j^N,N-bis(2-hidroxietil)-amino - 2,6 - dimetilaceta- nilida .Example 2 a) p-N, N-bis (2-hydroxyethyl) -amino-2,6-dimethylacetamylide.
Pesam-se num balão de fundo redondo, com um volume de 100 3 cm , 7,9 g (0,04 mole) de cloreto de £(2,6-dimetilfenil)-ami- 3 nocarbonilmetilo^J , 4,58 g (6,3 cm , 0,045 moles) de trietila- 3 mina, 4,24 g (0,04 moles) de dietanolamina, 50 cm de metil--isobutil-cetona e 0,1 g de iodeto de sódio. Ferve-se a mistura durante 3 horas e filtra-se enquanto está quente. Evapora--se o filtrado em vácuo para metade do seu volume e arrefece--se. Filtra-se o produto precipitado e seca-se. Rendimento 8,93 g (83,81%), ponto de fusão:77-802C.7.9 g (0.04 mole) of β- (2,6-dimethylphenyl) -aminocarbonylmethyl chloride (4.58 g, 0.08 mole) are weighed into a round-bottomed flask, (6.3 cm, 0.045 mol) of triethylamine, 4.24 g (0.04 mol) of diethanolamine, 50 cm of methyl isobutyl ketone and 0.1 g of sodium iodide. The mixture is boiled for 3 hours and filtered while hot. The filtrate is evaporated in vacuo to half its volume and cooled. The precipitate is filtered off and dried. Yield 8.93 g (83.81%), m.p.: 77-80Â ° C.
Cl o r i d r a to _ de _çy£ - > N - bis-( 2-cloroetil)-amino^j - 2,6- -dimetilacetanilida.The invention relates to a method for the preparation of a compound of formula (I): N-bis- (2-chloroethyl) amino] -2,6-dimethylacetanilide.
Equipa-se um balão de fundo redondo de três gargalos, com 3 um volume de 250 cm , com um termómetro, um funil conta-gotas 3 e um tubo de cloreto de cálcio. Pesam-se no mesmo 20 cm de 3 clorofórmio e 10,76 g (6,6 cm , 0,09 mole) de cloreto de timi- lo. Adicionam-se sob arrefecimento externo, a uma temperatura de 5SC, uma solução de 4,0 g (0,015 moles) de c=*C- , N-bis- -(2-hidroxietil)-amino ]] -2,6-dimetilacetanilida em 20 cm de clorofórmio. Depois de terminar a adição, deixa-se aquecer a mistura para a temperatura ambiente e depois agita-se durante 18 horas. Em seguida, arrefece-se a mistura reaccional para 3 10SC, adicionam-se 5 cm de metanol, e evapora-se em vácuo num banho a 30aC. 0 óleo residual é cristalizado com acetatoA three-necked round bottom flask of 3 250 cm volume is equipped with a thermometer, dropper funnel 3 and a calcium chloride tube. Weigh in the same 20 cm 3 chloroform and 10.76 g (6.6 cm, 0.09 mole) thymyl chloride. A solution of 4.0 g (0.015 mole) of C ,- N, N-bis- (2-hydroxyethyl) -amino] -2,6-dimethyl- dimethylacetanilide in 20 cm @ 3 of chloroform. After the addition is complete, the mixture is allowed to warm to room temperature and is then stirred for 18 hours. Then, the reaction mixture is cooled to 30 ° C, 5 cm of methanol is added, and the mixture is evaporated in vacuo in a 30 ° C bath. The residual oil is crystallized from ethyl acetate
de etilo, depois ponto de fusão : filtrado e seco. Rendimento : 3,03 g (59,4%), 118 a 120-C. c ) Dicioridrato de 1-|^3 - ( 2-metoxif enoxi )-2-hidroxipropiíj -4-^(2,6- dimetilfenil)-aminocarbonilmeti1 J - piperazinaethyl acetate, then melting point: filtered and dried. Yield: 3.03 g (59.4%), 118 to 120 ° C. c) 1- [3- (2-Methoxyphenoxy) -2-hydroxypropyl] -4- (2,6-dimethylphenyl) aminocarbonylmethyl] piperazine dihydrochloride
Pesam-se num balão de fundo redondo, com um volume deThey are weighed in a round bottom flask with a volume of
O 100 cm , 4,62 g (0,15 moles) de oí- QN,N-bis(2-cloroetil)- _ 3 -amino j -2,6-dimetilacetanilida, 40 cm de acetona aquosa a' 50%, 3,0 g (0,015 moles) de 1- Γ 3-(2-metoxifenoxi)-2-hidroxi]100 cm 4.62 g (0.15 mole) of N, N-bis (2-chloroethyl) -3-amino-2,6-dimethylacetanilide, 40 cm @ -1 of 50% aqueous acetone, 3.0 g (0.015 mol) of 1- [3- (2-methoxyphenoxy) -2-hydroxy]
3 L -propilamina e 3,5 g (4,87 cm , 0,035 moles) de trietilamina. Ferve-se a mistura durante 2 horas e depois remove-se a acetona em vácuo. Extrai-se a suspensão aquosa residual três ve-3 zes com 50 cm de cloreto de metileno, de cada vez. Seca-se o extracto e evapora-se. Submetem-se os 4,88 g do produto oleoso assim obtido a cromatografia numa coluna carregada com 150 g de Kieselgel 60 (0,040-0,063 mm) como absorvente, por ebulição com uma mistura 3 : 1 de clorofórmio e metanol. Os produtos eluidos são evaporados para se obterem 4,28 g de um óleo, 3 que são dissolvidos em 15 cm de ácido clorídrico metanólico e cristalizados pela adição de éter diisopropílico e seca-se. Rendimento : 4,35 g (58,0%), ponto de fusão : 229 a 230eC.3-L-propylamine and 3.5 g (4.87 cm, 0.035 mol) of triethylamine. The mixture is boiled for 2 hours and then the acetone is removed in vacuo. The residual aqueous suspension is extracted three times with 50 cm @ 3 of methylene chloride each time. The extract is dried and evaporated. The 4.88 g of the oily product thus obtained is subjected to chromatography on a column loaded with 150 g of Kieselgel 60 (0.040-0.063 mm) as an absorbent, by boiling with a 3: 1 mixture of chloroform and methanol. The eluate is evaporated to give 4.28 g of an oil, which is dissolved in 15 cm @ 3 of methanolic hydrochloric acid and crystallized by the addition of diisopropyl ether and dried. Yield: 4.35 g (58.0%), m.p. 229-230 ° C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU906953A HU209723B (en) | 1990-10-31 | 1990-10-31 | Process for producing of piperazine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PT99368A true PT99368A (en) | 1992-09-30 |
Family
ID=10972063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PT99368A PT99368A (en) | 1990-10-31 | 1991-10-29 | PROCESS FOR THE PREPARATION OF PIPERAZINE DERIVATIVES |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0483932A1 (en) |
| JP (1) | JPH04264078A (en) |
| KR (1) | KR920008018A (en) |
| AU (1) | AU8683091A (en) |
| CA (1) | CA2054544A1 (en) |
| CS (1) | CS329491A3 (en) |
| HU (1) | HU209723B (en) |
| NO (1) | NO914250L (en) |
| PL (1) | PL292227A1 (en) |
| PT (1) | PT99368A (en) |
| ZA (1) | ZA918636B (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0585500A1 (en) * | 1992-09-04 | 1994-03-09 | Merrell Dow Pharmaceuticals Inc. | Diaryl piperazineacetamides as antimuscarinic agents |
| US6677336B2 (en) | 2000-02-22 | 2004-01-13 | Cv Therapeutics, Inc. | Substituted piperazine compounds |
| US6638970B2 (en) | 2000-02-22 | 2003-10-28 | Cv Therapeutics, Inc. | Substituted alkylene diamine compounds |
| JP3980885B2 (en) * | 2000-02-22 | 2007-09-26 | スィーヴィー セラピューティクス インコーポレイテッド | Substituted piperazine compounds |
| US6552023B2 (en) | 2000-02-22 | 2003-04-22 | Cv Therapeutics, Inc. | Aralkyl substituted piperazine compounds |
| US6451798B2 (en) | 2000-02-22 | 2002-09-17 | Cv Therapeutics, Inc. | Substituted alkyl piperazine derivatives |
| US6677343B2 (en) | 2000-02-22 | 2004-01-13 | Cv Therapeutics, Inc. | Substituted piperazine compounds |
| KR100797835B1 (en) * | 2001-08-13 | 2008-01-24 | 주식회사 포스코 | Scale removing apparatus of pinch roll |
| US7205303B2 (en) | 2003-01-03 | 2007-04-17 | Cv Therapeutics, Inc. | Substituted heterocyclic compounds |
| AU2004252102A1 (en) | 2003-06-23 | 2005-01-06 | Gilead Palo Alto, Inc. | Urea derivatives of piperazines and piperidines as fatty acid oxidation inhibitors |
| JP2007514769A (en) * | 2003-12-18 | 2007-06-07 | シーブイ・セラピューティクス・インコーポレイテッド | 1-alkane-2-ol substituted piperazine and piperidine compounds |
| WO2006008753A1 (en) * | 2004-07-19 | 2006-01-26 | Unichem Laboratories Limited | Crystalline and amorphous form of ranolazine and the process for manufacturing them |
| WO2008047388A2 (en) * | 2006-10-20 | 2008-04-24 | Ind-Swift Laboratories Limited | Improved process for the preparation of ranolazine |
| WO2008139492A2 (en) * | 2007-05-15 | 2008-11-20 | Natco Pharma Limited | A process for the preparation of highly pure ranolazine base |
| US20110300218A1 (en) * | 2008-09-09 | 2011-12-08 | Actavis Group Ptc Ehf | Novel solid state forms of ranolazine salts |
| EP2356097A2 (en) * | 2008-10-15 | 2011-08-17 | Actavis Group PTC ehf. | Highly pure ranolazine or a pharmaceutically acceptable salt thereof |
| WO2010097805A1 (en) | 2009-02-24 | 2010-09-02 | Lupin Limited | A process for the preparation of ranolazine |
| EP3782992A1 (en) | 2015-03-10 | 2021-02-24 | Unichem Laboratories Limited | Novel process for the preparation of ranolazine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB662283A (en) * | 1948-08-02 | 1951-12-05 | Rhone Poulenc Sa | Improvements in or relating to piperazine compounds |
| US4567264A (en) * | 1983-05-18 | 1986-01-28 | Syntex (U.S.A.) Inc. | Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry |
-
1990
- 1990-10-31 HU HU906953A patent/HU209723B/en not_active IP Right Cessation
-
1991
- 1991-10-29 PT PT99368A patent/PT99368A/en not_active Application Discontinuation
- 1991-10-30 AU AU86830/91A patent/AU8683091A/en not_active Abandoned
- 1991-10-30 KR KR1019910019180A patent/KR920008018A/en not_active Application Discontinuation
- 1991-10-30 CA CA002054544A patent/CA2054544A1/en not_active Abandoned
- 1991-10-30 JP JP3285053A patent/JPH04264078A/en active Pending
- 1991-10-30 CS CS913294A patent/CS329491A3/en unknown
- 1991-10-30 NO NO91914250A patent/NO914250L/en unknown
- 1991-10-30 ZA ZA918636A patent/ZA918636B/en unknown
- 1991-10-30 PL PL29222791A patent/PL292227A1/en unknown
- 1991-10-31 EP EP91202836A patent/EP0483932A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04264078A (en) | 1992-09-18 |
| AU8683091A (en) | 1992-05-07 |
| CS329491A3 (en) | 1992-05-13 |
| NO914250L (en) | 1992-05-04 |
| ZA918636B (en) | 1992-08-26 |
| KR920008018A (en) | 1992-05-27 |
| NO914250D0 (en) | 1991-10-30 |
| CA2054544A1 (en) | 1992-05-01 |
| PL292227A1 (en) | 1992-06-26 |
| HU209723B (en) | 1994-10-28 |
| HU906953D0 (en) | 1991-05-28 |
| HUT62278A (en) | 1993-04-28 |
| EP0483932A1 (en) | 1992-05-06 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| BB1A | Laying open of patent application |
Effective date: 19920512 |
|
| FC3A | Refusal |
Effective date: 19990113 |